1-[(Hydroxyamino)methyl]-6-aryl-4H-s-triazolo[4,3-a][1,4]benzodiazepines

ABSTRACT

Compounds of the formula ##STR1## wherein R o  is hydrogen or alkyl of 1-3 carbon atoms, inclusive; wherein R 1  is hydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl or alkylthio in which the alkyl moiety is of 1 to 3 carbon atoms, inclusive; and wherein R 2  is phenyl, o-chlorophenyl, o-fluorophenyl, 2,6-difluorophenyl or 2-pyridyl, or the pharmaceutically acceptable acid addition salts thereof. The compounds are useful as sedatives, antianxiety agents, antidepressants, anticonvulsives and muscle-relaxing agents.

This is a division of application Ser. No. 666,902, filed Mar. 15, 1976.

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION

This invention is directed to new1-[(aminooxy)methyl]-6-substituted-4H-s-triazolo[4,3-a][1,4]benzodiazepines,intermediates, and the processes of production thereof.

The novel compounds and the processes of the production therefor can beillustratively represented as follows: ##STR2## and if R' and/or R" isof 2 or 3 carbon atoms, inclusive, ##STR3## wherein R' and R" are alkylof 1 to 3 carbon atoms, inclusive; wherein R'" corresponds to R' or R"with the proviso that R" or R' has 2 or 3 carbon atoms, inclusive;wherein R₁ is hydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl oralkylthio in which the alkyl moiety is of 1 to 3 carbon atoms,inclusive; and wherein R₂ is phenyl, o-chlorophenyl, o-fluorophenyl,2,6-difluorophenyl, or 2-pyridyl.

Compound IIIB is produced from IV if R' and R" are methyl, if R' and/orR" are alkyl of 2 to 3 carbon atoms, then simultaneously with IIIBcompound V is obtained. Compounds of formula VA: ##STR4## wherein R₁ andR₂ are defined as herein above and wherein R_(o) is hydrogen or alkyl of1 to 3 carbon atoms, inclusive; can also be prepared by reactingcompound I with a nydroxyamine of the formula: ##STR5##

The invention also embraces the pharmacologically acceptable additionsalts of the compounds IIIA and IIIB as well as those of compounds IV, Vand VA and the Schiff's bases derived from compound IIIA having theformula VI: ##STR6## wherein R₁ and R₂ are defined as above and R₅ andR₆ are hydrogen or alkyl as defined above.

Thus the invention comprises compounds of formula III (composite formulaof IIIA and IIIB): ##STR7## wherein R'o and R"o are hydrogen or alkyl of1 to 3 carbon atoms, inclusive; R₁ is hydrogen, fluoro, chloro, bromo,nitro, trifluoromethyl, or alkylthio in which the alkyl moiety is of 1-3carbon atoms, inclusive; R₂ is phenyl, o-chlorophenyl, o-fluorophenyl,2,6-difluorophenyl or 2-pyridyl, and the pharmacologically acceptableacid addition salts thereof.

The invention further comprises the Schiff's bases of formula VI, thehydroxyamines of formulae V and VA and the intermediates of formula IVas well as the pharmacologically acceptable acid addition salts ofcompounds of formulae IV, V, VA, and VI.

The invention also comprises the processes of production for compoundsIII, IV, V, VA, and VI.

The process to produce the compounds of formula IIIA (i.e. compounds offormula III, wherein R'o and R"o are both hydrogen) comprises: treatinga compound of formula I with N-hydroxyphthalimide in the presence of atertiary amine base at 0° to 100° C. to obtain compound II; and treatingcompound II with hydrazine or its hydrate between 25°-100° C. to obtaincompound IIIA.

The process to produce the compounds of formula IIIB (i.e. compounds offormula III, wherein R'o and R"o are alkyl of 1 to 3 carbon atoms,inclusive) comprises: treating compound I with a N,N-dialkylhydroxyamineand an acid neutralizing agent at 25° to 100° C. to obtain compound IV;heating compound IV between 140° to 200° C. to obtain compound IIIB, andif R' and/or R" is ethyl, propyl, or isopropyl, compound V.

Compounds of formula VA (compounds of formula V in which R'" is alsohydrogen) are prepared by condensing a compound of formula I with anunsubstituted or N-monoalkylhydroxyamine.

The process to produce the compounds of formula VI comprises: condensinga compound of formula IIIA with an aldehyde or keto compound attemperatures of 0 to 100° C.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Alkyl groups of 1 to 3 carbon atoms, inclusive, means methyl, ethyl,propyl, or isopropyl.

The more preferred compounds of formula III have the specific structureIIIC: ##STR8## wherein R'" is hydrogen, methyl, or ethyl; wherein R₁ ishydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, or alkylthio inwhich the alkyl moiety is of 1 to 3 carbon atoms inclusive; and whereinR₂ is phenyl, o-chlorophenyl, o-fluorophenyl, 2,6-difluorophenyl or2-pyridyl; and the pharmaceutically acceptable acid addition saltsthereof.

Similarly more preferred are the species in the series of compounds IV,V and VA which have the formulae IVA and VB: ##STR9## wherein R₁ ishydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, or alkylthio inwhich the alkyl moiety is of 1 to 3 carbon atoms, inclusive; wherein R₂is phenyl, o-chlorophenyl, o-fluorophenyl, 2,6-difluorophenyl, or2-pyridyl; and wherein R₄ is methyl or ethyl, and the pharmaceuticallyacceptable acid addition salts thereof.

The most preferred compounds of formula III have the specific structureIIID: ##STR10## wherein R₁ is hydrogen, fluoro, chloro, ortrifluoromethyl; wherein R'"o is hydrogen, methyl, or ethyl; and whereinR₃ is hydrogen, chloro, or fluoro; and the pharmaceutically acceptableacid addition salts thereof.

Similarly most preferred are the species in the series of compounds IV,V and VA which have the formulae IVB and VC: ##STR11## wherein R'1 ishydrogen, fluoro, chloro, or trifluoromethyl; wherein R₃ is hydrogen,chloro, or fluoro; and wherein R₄ is methyl or ethyl, and thepharmaceutically acceptable acid addition salts thereof.

The compounds of formula III (inclusive IIIA, B, C, and D), IV(inclusive of IVA and B), V (inclusive of VA, VB, and VC) and VI and thepharmacologically acceptable acid addition salts thereof, are usefulsedative tranquilization and anti-anxiety agents for mammals, includingman and birds. They also have anti-depressant activity and can be thusused in man for the treatment of anxieties and endogenous and exogenousdepressions.

The pharmacologically acceptable acid addition salts of the compoundsIII, IV, V, and VI including the preferred subclasses, include thehydrochlorides, hydrobromides, hydriodides, sulfates, phosphates,acetates, propionates, lactates, maleates, malates, succinates,tartrates, and the like.

The tranquilization and sedative activity of the new compounds offormulae III, IV, V, and VI (including the preferred subclasses) andtheir pharmacologically acceptable acid addition salts are tested inmice as follows:

Chimney test: [Med. Exp. 4, 145 (1961)]: The test determines the abilityof mice to back up and out of a vertical glass cylinder within 30seconds. At the effective dosage, 50% of the mice failed doing it.

Dish test: Mice in Petri dishes (10 cm. diameter, and 5 cm. high),partially embedded in wood shavings, climb out in a very short time,when not treated. Mice remaining in the dish for more than 3 minutesindicates tranquilization. ED₅₀ equals the dose of test compound atwhich 50% of the mice remain in the dish.

Pedestal test: The untreated mouse leaves the pedestal in less than aminute to climb back to the floor of the standard mouse box.Tranquilized mice will stay on the pedestal for more than one minute.

Nicotine antagonism test: Mice in a group of 6 are injected with thetest compound. Thirty minutes later the mice including control(untreated) mice are injected with nicotine salicylate (2 mg./kg.). Thecontrol mice show overstimulation, i.e. (1) running convulsions,followed by (2) tonic extensor fits; followed by (3) dealth.Pretreatment with an active sedative or tranquilizing compound protectsmice against (2) and (3).

TESTING FOR ANXIETY

Prolongation of Hypoxic survival: Pretreatment of mice exposed to thestress of progressive hypoxia and hypercapnia with anxiolytics resultsin a prolongation of survival.

Male CF-1 derived mice are used in these studies. Thirty minutes afterintraperitoneal pretreatment (test agent suspended in 0.25%methylcellulose or vehicle alone, 1 cc/100 gm. body weight) the mice areplaced singly in 125 ml. Erlenmeyer flasks. The receptacles were tightlystoppered and the survival time (time from stoppering to the lastrespiratory effort) of each animal noted. Each compound is tested atthree or more doses spaced at 0.3 log intervals. Six mice are used perdose with six vehicle injected controls run simultaneously. The mean(15-18 minutes) and standard deviation (1-2 minutes) of the survivaltime for the vehicle treated mice are used to convert the data to aquantal form in the following manner. All survival times that differedfrom the mean of the controls by more than 2 standard deviations arescored as a drug effect. ED₅₀ s are calculated by the method of Spearmanand Karber (Finney, D. J., Statistical Method in Biological Assay,Hafner Publ., Co. N.Y., 1952). The novel compounds of formula III(including compounds IIIA, IIIB, IIIC, IIID), IV (including IVA, IVB), V(including VA, VB, VC), and VI and pharmacologically acceptable acidaddition salts thereof also have anti-depressant activity.

The main function of an anti-depressant is to return the depressedindividual to normal function. This should be carefully differentiatedfrom psychic stimulants such as the amphetamines which produceoverstimulation in the normal individual.

Many different methods have been and are used to evaluateanti-depressent activity. In general these methods involve antagonism toa depressant such as reserpine or tetrabenazine or a synergisticincrease of the toxicity of certain compounds (i.e., yohimbine or3,4-dihydroxyphenylalanine) and comparison of the drug action of the newcompound with other known anti-depressants. No single test alone candetermine whether or not a new compound is an antidepressant or not, butthe profile evidenced by various tests will establish thatanti-depressent action is present. A number of such tests are describedbelow.

Hypothermic tests with oxotremorine[1-[4-(pyrrolidinyl)-2-butynyl[-2-pyrrolidinone[.

Oxotremorine (as well as apomorphine and tetrabenazine) produceshypothermic responses in mice. This response is blocked byanticholinergics and anti-depressants such as atropine and imipramine.

Oxotremorine produced a very pronounced hypothermia which reaches a peak60 minutes after administration. When administered at 0.6 mg./kg. thebody temperature of a mouse is decreased about 13° F. (when the mouse iskept at room temperature). This temperature decrease is antagonized byanti-depressants, e.g., desipramine, imipramine, and amitriptyline.

The present compounds are tested as follows. Groups of four male miceweighing 18-22 g. (Strain CF1, Carworth Farms) are injectedintraperitoneally with the test compound prepared in 0.25%methylcellulose and placed in plastic cages. Thirty minutes later 1mg./kg. oxotremorine hydrochloride is injected subcutaneously. The miceare placed in a refrigerator maintained at 19° C. Thirty minutes laterthe intraperitoneal temperature is measured using a thermistor probe. Anincrease of 4° F. in the body temperature of the treated mouse(oxotremorine and test compound) over the control mouse (oxotremorinetreated only) is indicative of antidepressive activity.

THe same compounds were also tested for potentiation of yohimbineaggregation toxicity. The LD₅₀ of yohimbine hydrochloride in mice is 45mg./kg. i.p. Administration of 20 mg./kg. of yohimbine hydrochloride isnon-lethal. If an antidepressant is administered prior to the yohimbinehydrochloride (20 mg./kg.) the lethality of the yohimbine hydrochlorideis increased.

Eight male CF1 mice, 18-22 g., are injected with yohimbine hydrochloridein saline solution. After four hours the LD₅₀ s are determined. Groupsof eight mice are injected with the antidepressant 30 minutes before theadministration of yohimbine hydrochloride [YCl;] (20 mg./kg.). No miceor only one mouse is killed from 20 mg./kg. of [YCl]. If [YCl] isadministered in the presence of an anti-depressent an increase in thetoxicity of [YCl] is found. The ED₅₀ is the dosage of test compoundwhich causes 50% of the mice to die.

Also the compounds are tested for the potentiation of apomorphinegnawing. A group of 4 mice (male, CF1, 18-22 g.) are administered thetest compound intraperitoneally 1 hour prior to the subcutaneousinjection of apomorphine hydrochloride 10 mg./kg. The mice are thenplaced in a plastic box (6 × 11 × 5 inches) lined at the bottom with acellophane-backed, absorbent paper. The degree of damage to the paper atthe end of 30 minutes is scored from zero to 4. The scores 2 to 4indicate that the compound is a potentiator of apomorphine in this test.

Results in the above tests show that the compounds of formulae III to VIand the pharmacologically acceptable acid addition salts thereof can beused as anti-depressants, sedatives, and anti-anxiety drugs in mammalsto achieve normalcy in the depressed or anxious individual.

The pharmaceutical forms of compounds of formulae III to VI and saltsthereof contemplated by this invention include pharmaceuticalcompositions suited for oral, parenteral, and rectal use, e.g., tablets,powder packets, cachets, dragees, capsules, solutions, suspensions,sterile injectable forms, suppositories, bougies, and the like. Suitablediluents or carriers such as carbohydrates, lactose, proteins, lipids,calcium phosphate, cornstarch, stearic acid, methylcellulose and thelike may be used as carriers or for coating purposes. Water or oils suchas coconut oil, sesame oil, safflower oil, cottonseed oil, and peanutoil, may be used for preparing solutions or suspensions of the activedrug. Sweetening, coloring and flavoring agents may be added.

For mammals, food premixes with starch, oatmeal, dried fishmeat,fishmeal, flour, and the like can be prepared.

As antidepressants, sedatives, and antianxiety agents the compounds offormulae III through VI and their pharmacologically acceptable acidaddition salts can be used in dosages of 0.02-1 mg./kg. and preferably0.02-0.5 mg./kg. in oral or injectable preparations, as described above,to alleviate depression and anxieties occurring in stressful situations.Such situations are those for example, when animals are in travel orchanging ownerships or are temporarily put into kennels, while theirowners are absent from home. The larger mammals (10 kg. or more) respondbest to the low dosages of the above dosage ranges.

The starting materials of formula I of this invention are1-haloalkyl-6-phenyl or6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepines, which aredescribed in British Specification No. 1,331,917 or are synthesized asshown in the Preparations.

In carrying out the process of this invention to synthesize compounds ofthe structure IIIA, a selected starting compound I is reacted withN-hydroxyphthalimide in the presence of a tertiary amine base, e.g.triethylamine, tripropylamine, diethylpropylamine, pyridine,N-methylpiperidine or the like, with triethylamine preferred. Thereaction can be carried out between 0° to 100° C. during a period of 1to 24 hours. Preferably room temperature, 18°-30° C. is used whereby thereaction is completed in 2 to 10 hours. Also preferred is an inertorganic solvent such as dimethylformamide, diethylformamide,dimethylacetamide, dimethyl sulfoxide or hexamethyl phosphoric acidtriamide. The product II is isolated and purified by conventional means,such as evaporating the solvent, or extracting product II, washing it,crystallizing or chromatographing it, and the like.

Compound II is then treated with hydrazine, hydrazine hydrate, or aprimary alkyl amine, e.g. methyl, ethyl, or propyl amine or the like ina lower alkanol of 1 to 3 carbon atoms at 25°-100° C. Methanol, ethanol,or propanol are the preferred solvents, but tetrahydrofuran, dioxane,diethylether and the like can also be used. After the reaction iscompleted (1 to 10 hours), the product IIIA is obtained by conventionalprocedures, e.g. extraction, chromatography, crystallization and thelike.

To obtain the products IV, a starting compound of formula I is treatedwith a N, N,N-dialkylhydroxyamine in which the alkyl groups are of 1 to3 carbon atoms, inclusive. In the preferred embodiment of this inventionan inert organic solvent is used e.g. dimethylformamide,dimethylacetamide, tetrahydrofuran, dioxane, dimethylsulfoxide,hexamethyl phosphoric acid triamide, methanol, ethanol, propanol, or thelike at a temperature of 25° to 100° C. for 1 to 24 hours. Preferably abase is used to neutralize the hydrogen halide which is liberated duringthe reaction. Alkali metal hydroxides, e.g. sodium or potassiumhydroxide; hydrides; carbonates or alkoxides of 1 to 3 carbon atoms,inclusive or the like can be used.

After the reaction is completed, the product IV is obtained byconventional procedures, e.g. extraction, chromatography,crystallization, and the like.

In order to obtain the products of formulae IIIB and V, the product offormula IV needs merely to be pyrolyzed at or above its melting pointtemperature. Usually temperatures of 140° to 200° C. are sufficient.High boiling liquids such as xylene, decaline, or a mineral oil may alsobe employed to produce a uniform temperature in the reaction vessel.Reduced pressure or a nitrogen atmosphere are generally advantageous inthis reaction. If the dialkyl hydroxyamine used to prepare compound IVin the prior reaction, had more than 1 carbon atom in the alkyl groups,compounds of formula V are obtained together with compounds of formulaIIIB. The obtained compounds, either IIIB or IIIB and V are isolated andpurified by standard procedures such as extracting, chromatography,crystallization and fractional crystallization, and the like.

If compounds of formula VA are desired a compound of formula I isreacted with an unsubstituted or N-monoalkylhydroxyamine in which thealkyl group is of 1 to 3 carbon atoms, inclusive. Under the sameconditions as described above the reaction with dialkyl hydroxyaminedescribed above 25° to 100° C. and 1 to 24 hours reaction time, in anorganic solvent e.g. dimethylformamide, dimethylsulfoxide,hexamethylphosphoric acid amide or tetrahydrofuran, with an added basesuch as sodium hydride.

Compounds of formula VI are produced by the usual methods of synthesisof Schiff's bases. Generally a selected compound of formula IIIA isheated with an aldehyde or ketone. In the preferred embodiment of thisinvention, e.g. solvents such as methanol, ethanol, 1- or 2-propanol,dioxane, tetrahydrofuran, together with acetic acid are employed and thereaction mixture is kept at temperatures of 25° to the refluxtemperature of the mixture for 0.5 to 6 hours. If acetic acid is used,the mixture is first neutralized and then extracted with an organicsolvent. From the extracts the product VI is obtained and purified byconventional procedures, such as evaporation, crystallization orchromatography.

The following preparations and examples are illustrative of theprocesses and products of the present invention, but are not to beconstrued as limiting.

Preparation 1: 7-Bromo-5 -(2-pyridyl)-3H-1,4-benzodiazepin-2-ylhydrazine

A mixture of7-bromo-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-thione (U.S.Pat. No. 3,734,922) (16.01 g., 10.048 mole), hydrazine hydrate (7.51 g,0.15 mole) and methanol (400 ml.) was stirred at ambient temperature for19 hours with a stream of nitrogen bubbling through the mixture. Theresulting solid was collected by filtration, washed with methanol anddried to give 13.6 g. of 7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-ylhydrazine of melting point 224°-225° C. with decomposition. Theanalytical sample was recrystallized from methanol-chloroform and had amelting point of 224°-226° C. (dec.).

Anal. calcd. for C₁₄ H₁₂ N₄ Br: C, 50.93; H, 3.66; Br, 24.20; N, 21.21.Found: C, 50.77; H, 3.82; Br, 24.22; N, 21.29.

Preparation 2:8-Bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine(I)

7-Bromo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl hydrazine (4.95 g.,0.015 mole) is slowly added to 50 ml. of acetic acid with externalcooling. A solution of 1.69 g. of chloroacetyl chloride in 25 ml. ofacetic acid is then added during about ten minutes, the solution isstirred at room temperature for about 1.5 hours and 1.23 g. of sodiumacetate added with additional stirring for about 30 minutes. The mixtureis then refluxed for about 3.25 hours. This mixture is cooled, pouredinto ice water and concentrated to a small volume, then diluted withwater, neutralized with sodium bicarbonate and extracted withchloroform. The extract is dried over anhydrous magnesium sulfate,concentrated, and the residue chromatographed on a column of 250 g. ofsilica gel, with 5% methanol-95% chloroform. The product obtained fromthe column is8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Preparation 3: 8-Chloro-1-(bromomethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine

Following the procedure of Preparation 2, but substituting bromoacetylbromide for chloroacetyl chloride and using7-chloro-5-(2-pyridyl)-3H-1,4-benzodiazepine-2-yl hydrazine yields8-chloro-1-(bromomethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Preparation 4:8-Bromo-1-(bromomethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine(I)

Following the procedure of Preparation 2, but substituting bromoacetylbromide for chloroacetyl chloride, yields8-bromo-1-(bromomethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Preparation 5: 2-(2-Amino-5-thiocyanobenzoyl)pyridine

A suspension of 2-(2-aminobenzoyl)pyridine [K. Schofield, J. Chem. Soc.2408 (1949)] (79.2 g., 0.40 mole) and sodium thiocyanate (111.4 g., 1.38mole) in methanol (300 ml.) was cooled to 0° and treated, dropwise witha cold solution of bromine (81.9 g., 0.51 mole) in methanol (105 ml.,saturated with sodium bromide). The resulting mixture was stirred for anadditional 1 hour at 0°, allowed to come to ambient temperature andpoured into 2 liters of cold water. The mixture was neutralized with a20% solution of sodium carbonate in water, and extracted with ethylacetate. The extract was dried over anhydrous sodium sulfate andconcentrated in vacuo. The solid residue was dissolved in hot methanoland decolorized with Darco (activated carbon). The resulting solutionwas diluted with water and allowed to crystallize at about 4° C. to give78 g. (76.5%) of 2-(2-amino-5-thiocyanobenzoyl)pyridine of melting point103.5°-105° C. The analytical sample had melting point 102°-103.5° C.

Anal. calcd. for C₁₃ H₉ N₃ OS: C, 60.92; H, 3.56; N, 16.46; S, 12.56;Found: C, 61.02; H, 3.81; N, 16.46; S, 12.57.

Preparation 6: 2-(2-Amino-5 -methylthiobenzoyl)pyridine

A suspension of 2-(2-amino-5-thiocyanobenzoyl)pyridine (0.5 g., 0.002mole) in ethanol (5 ml.) was warmed to 50° and treated with sodiumhydrosulfite (0.56 g., 0.0032 mole) and 10% sodium hydroxide (3.3 ml.),alternately, in portions. The temperature of the mixture was raised to80° and then cooled to 40°. It was then treated, dropwise, with 0.36 g.(0.0028 mole) of dimethyl sulfate. The mixture was stirred at ambienttemperature for 1 hour and concentrated in vacuo to remove ethanol. Theresulting mixture was diluted with water and extracted with benzene. Theextract was washed with water and brine, dried over anhydrous potassiumcarbonate and concentrated. The oily residue was chromatographed oversilica gel (100 g.) with mixtures of methylene chloride, acetone andSkellysolve B (hexanes) to give 0.25 g. of2-(2-amino-5-methylthiobenzoyl)pyridine as an oil.

Preparation 7:7-Methylthio-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one

A stirred solution of 2-[2-amino-5-(methylthio)benzoyl]pyridine (0.0249mole) in acetic acid (250 ml.) was treated during 5 minutes with 5.02 g.of bromoacetyl bromide. This mixture was kept at ambient temperature for2 hours and concentrated in vacuo. The residue was carefully treatedwith about 150 ml. of liquid ammonia. The ammonia was allowed toevaporate and the residue was mixed with water and extracted withmethylene chloride. The extract was dried over anhydrous sodium sulfateand concentrated. The residue was crystallized to give7-methylthio-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one.

Preparation 8:7-Methylthio-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-thione.

A stirred solution of7-methylthio-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepin-2-one(0.0206 mole) in dry pyridine (400 ml.) was treated with phosphoruspentasulfide (5.05 g.), warmed, under nitrogen, at 110°-120° C. for 1hour, cooled and concentrated in vacuo. Residual pyridine was removed bythe successive addition of xylene and toluene to the residue withconcentration after each addition. The resulting residue was mixed withdilute sodium carbonate and extracted with chloroform. The chloroformextract was washed with brine, dried over anhydrous sodium sulfate andconcentrated. The residue was crystallized to give7-methylthio-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-thione.

Preparation 9: 7-Methylthio-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-ylhydrazine

According to the procedure of Preparation 1,7-methylthio-1,3-dihydro-5-(2-pyridyl)-2H-1,4-benzodiazepine-2-thione isreacted with hydrazine hydrate in methanol to give7-methylthio-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl hydrazine.

Preparation 10:8-Methylthio-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine(I)

According to the procedure of Preparation 2,7-methylthio-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl hydrazine wasreacted with chloroacetyl chloride in acetic acid to give8-methylthio-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 1:8-Chloro-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine

A stirred solution of N-hydroxyphthalimide (5.38 g.) and triethylamine(9.15 ml.) in dimethylformamide (100 ml.) was treated with8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine(10.3 g.) and kept at ambient temperature, under nitrogen, for 3 hours35 minutes. it was poured into cold water, stirred for a few minutes,and filtered. The solid was washed with water and chloroform and driedto give 9.88 g. of8-chloro-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine,melting point 260°-261° C. dec. The filtrate was extracted withchloroform. The extract was washed with brine, dried over anhydroussodium sulfate and concentrated. The residue was mixed with xylene andagain concentrated in vacuo to remove residual dimethylformamide. Thesolid residue was mixed with ethanol and filtered. The solid was washedwith ethanol and dried to give 3.02 g. of additional product of meltingpoint 255°-255.5° C. dec. The analytical sample was recrystallized fromethanol-chloroform and had melting point 256.5°-257.5° C. (dec).

Anal. calcd. for C₂₅ H₁₆ ClN₅ O₃ : C, 63.90; H, 3.43; N, 14.90. Found:C, 63.57; H, 3.67; N, 14.95.

Example 2:1-[(Aminooxy)methyl]-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine

A stirred suspension of8-chloro-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine(9.4 g., 0.02 mole) in absolute ethanol (100 ml.) was treated withhydrazine hydrate (1.45 ml.) and warmed, under nitrogen, at a bathtemperature at 70° C. for 3 hours. The mixture was cooled in an ice bathand filtered. The solid was washed with ethanol and methylene chloride.The combined filtrate was concentrated in vacuo; the residue was mixedwith water and extracted with methylene chloride. The extract was washedwith water, dried over anhydrous sodium sulfate and concentrated. Theresidue was dissolved in chloroform-ethyl-acetate and filtered through asmall pad of silica gel. The filtrate was crystallized frommethanol-ethylacetate to give1-[(aminooxy)methyl]-8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepinein three crops: 1.95 g. of melting point 190°-191.5° C.; 0.89 g. ofmelting point 183°-186° C.; 0.285 g. of melting point 183°-186° C. Theanalytical sample had a melting point 191°-192° C.

Anal. calcd. for C₁₇ H₁₄ ClN₅ O: C, 60.09; H, 4.15; Cl, 10.43; N, 20.61;Found: C, 59.54; 59.90; H, 4.16; 4.45; Cl, 10.45; N, 20.51; 20.44.

Example 3:8-Chloro-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiapepine

In the manner given in Example 1, N-hydroxyphthalimide and triethylaminein dimethylacetamide is treated with8-chloro-6-(o-chlorophenyl)-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineto give8-chloro-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 4:1-[(Aminooxy)methyl]-8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 2, a solution of hydrazine hydrate inethanol is reacted at 65° C. with8-chloro-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepineto give1-[(aminooxy)methyl]-8-chloro-6-(o-chlorophenyl)-4-H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 5:8-Fluoro-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3][1,4]benzodiazepine

In the manner given in Example 1, N-hydroxyphthalimide and triethylaminein dimethylacetamide is treated with8-fluoro-6-phenyl-1-(Chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineto give8-fluoro-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 6:1-[(Aminooxy)methyl]-8-fluoro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 2, a solution of hydrazine hydrate inethanol is reacted at 65° C. with8-fluoro-1-[(phthalimidooxy)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepineto give1-[(aminooxy)methyl]-8-fluoro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 7:8-Trifluoromethyl-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 1, N-hydroxyphthalimide and triethylaminein dimethylacetamide is treated with8-trifluoromethyl-6-(o-chlorophenyl)-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineto give8-trifluoromethyl-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 8:1-[(Aminooxy)methyl]-8-trifluoromethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 2, a solution of hydrazine hydrate inethanol is reacted at 65° C. with8-trifluoromethyl-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepineto give1-[(aminooxy)methyl]-8-trifluoromethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 9:8-Nitro-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 1, N-hydroxyphthalimide and triethylaminein dimethylacetamide is treated with 8-nitro-6-(o-chlorophenyl)-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give8-nitro-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 10:1-[(Aminooxy)methyl]-8-nitro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 2, a solution of hydrazine hydrate inethanol is reacted at 65° C. with8-nitro-1-[(phthalimidooxy)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineto give1-[(aminooxy)methyl]-8-nitro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 11:8-Methylthio-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 1, N-hydroxyphthalimide and triethylaminein dimethylformamide is treated with8-methylthio-6-phenyl-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineto give8-methylthio-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 12:1-[(Aminooxy)methyl]-8-methylthio-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 2, a solution of hydrazine hydrate inethanol is reacted at 65° C. with8-methylthio-6-phenyl-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepineto give1-[(aminooxy)methyl]-8-methylthio-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 13:8-Bromo-6-(2-pyridyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 1, N-hydroxyphthalimide and triethylaminein dimethylacetamide is treated with8-bromo-6-(2-pyridyl)-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineto give8-bromo-6-(2-pyridyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 14:1-[(Aminooxy)methyl]-8-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 2, a solution of hydrazine hydrate inethanol is treated at 65° C. with8-bromo-1-[(phthalimidooxy)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineto give1-[(aminooxy)methyl]-8-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

In the same manner given in Example 2 combined with Example 1, other6-phenyl- or respectively6-(2-pyridyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepinesof formula IIIA can be prepared. Representative compounds thus obtainedinclude:

8-bromo-6-phenyl-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(o-fluorophenyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(2,6-difluorophenyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

6-(o-chlorophenyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

6-(o-fluorophenyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-nitro-6-phenyl-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-bromo-6-(o-chlorophenyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-trifluoromethyl-6-phenyl-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(o-chlorophenyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(o-fluorophenyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

7-chloro-6-(o-chlorophenyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-bromo-6-phenyl-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

10-nitro-6-(o-fluorophenyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-trifluoromethyl-6-(o-chlorophenyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(2-pyridyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(2-pyridyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-nitro-6-(2-pyridyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-trifluoromethyl-6-(2-pyridyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

7-nitro-6-(2-pyridyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-bromo-6-(2-pyridyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

10-chloro-6-(2-pyridyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-ethylthio-6-(2-pyridyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-propylthio-6-(o-chlorophenyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-isopropylthio-6-(2,6-difluorophenyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-methylthio-6-(o-chlorophenyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

6-phenyl-1-[(aminooxy)methyl]-4-H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-methylthio-6-(2-pyridyl)-1-[(aminooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;and the like.

Example 15:8-Chloro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine,N¹ -oxide, hydrate

A stirred solution of N,N-dimethylhydroxylamine (3.67 g., 0.06 mole) indry dimethylformamide (50 ml. is cooled in an ice bath, under nitrogen,and treated with a 57% mineral oil suspension of sodium hydride (0.84g., 0.02 mole). The mixture is kept at ambient temperature for 1 hour (aprecipitate formed) and then cooled in an ice bath and treated with8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine(6.86 g., 0.02 mole). The mixture is kept at ambient temperature for 2hours and concentrated in vacuo. Last traces of dimethylformamide areremoved from the residue by the successive addition and distillation ofxylene, toluene, and benzene. The resulting material is chromatographedon silica gel (250 g.) with methanol. The product thus obtained iscrystallized from methanol-ethyl acetate (following activated charcoaltreatment) to give8-chloro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine,N¹ -oxide, hydrate in three crops: 3.377 g. of melting point160.5°-162.5° C; 1.145 g. of melting point 160°-162° C.; and 0.785 g. ofmelting point 160°-162° C. The analytical sample had a melting point of157.5°-158.5° C. with decomposition.

Anal. calcd. for C₁₉ H₁₈ ClN₅ O: C, 62.04; H, 4.93; Cl, 9.64; N, 19.04.Found: C, 59.89; H, 5.15; Cl, 8.69; 9.35; N, 18.77; H₂ O, 3.22. Anal.calcd. for 3.22% H₂ O; C, 61.88; H, 4.96; Cl, 8.98; 9.66; H, 19.39.

Example 16:8-Chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine,N¹ -oxide, hydrate

A stirred, ice cold solution of N,N-diethylhydroxylamine (50 ml.) indimethylformamide (50 ml.) under nitrogen, was treated with a 57%suspension of sodium hydride in mineral oil (1.39 g., 0.033 mole). Themixture was kept at ambient temperature for 55 minutes, cooled in an icebath and treated with 8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine (10.3 g., 0.03 mole). This mixture was keptat ambient temperature for 18 hours and poured into ice water. Theresulting mixture was saturated with sodium chloride and extracted withchloroform. The extract was washed with brine, dried over anhydroussodium sulfate and concentrated. The residue was mixed with xylene andconcentrated in vacuo, the resulting material was crystallized from wetmethanol-ethyl acetate to give8-chloro-1-[(diethylamino)-methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N¹ -oxide dihydrate in two crops: 5.91 g.,of melting point 137.5°-139.5° C. dec. and 1.16 g., of melting point135°-137.5° C. The analytical sample had a melting point of 135°-137.5°C. dec.

Anal. calcd. for C₂₁ H₂₆ ClN₅ O₃ : C, 58.40; H, 6.07; Cl, 8.21; N,16.22; H₂ O, 8.34. Found: C, 58.22; H, 6.00; Cl, 8.17; N, 16.28; H₂ O,7.86.

Example 17:8-Methylthio-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N¹ -oxide

In the manner given in Example 15,8-methylthio-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepineis treated with a cold mixture of N,N-dimethylhydroxylamine and sodiumhydride in dimethylformamide to give8-methylthio-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N¹ -oxide.

Example 18:8-Chloro-1-[(diethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide

In the manner given in Example 15, 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine is treatedwith a cold mixture of N,N-diethylhydroxylamine and sodium hydride indimethylformamide to give8-chloro-1-[(diethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide.

Example 19:8-Chloro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide

In the manner given in Example 16, a solution ofN,N-dimethylhydroxylamine in dimethylformamide is treated with sodiumhydride suspended in mineral oil, and the mixture is treated with8-chloro-1-(bromomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineto give8-chloro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide.

Example 20:8-Fluoro-1-[(ethylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide

In the manner given in Example 15,8-fluoro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepineis treated with a cold mixture of N-ethyl-N-methylhydroxyamine andsodium hydride in dimethylformamide to give8-fluoro-1-[(ethylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide.

Example 21:8-Fluoro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide

In the manner given in Example 16, a solution ofN,N-dimethylhydroxylamine in dimethylformamide is treated with sodiumhydride suspended in mineral oil, and the mixture is treated with8-fluoro-1-(bromomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepineto give8-fluoro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine,N¹ -oxide.

Example 22:8-Trifluoromethyl-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide

In the manner given in Example 15,8-trifluoromethyl-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepineis treated with a cold mixture of N,N-diethylhydroxylamine and sodiumhydride in dimethylformamide to give8-trifluoromethyl-1-[(diethylamino)-methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide.

Example 23:8-Nitro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,N¹ -oxide

In the manner given in Example 16, a solution ofN,N-dimethylhydroxylamine in dimethylformamide is treated with sodiumhydride, suspended in mineral oil, and the mixture is treated with8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineto give8-nitro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,N¹ -oxide.

Example 24:8-Nitro-1-[(dipropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,N¹ -oxide

In the manner given in Example 15,8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepineis treated with a cold mixture of N,N-dipropylhydroxylamine and sodiumhydride in dimethylformamide to give8-nitro-1-[(dipropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,N¹ -oxide.

Example 25:8-Nitro-1-[(diisopropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,N¹ -oxide

In the manner given in Example 16, a solution ofN,N-diisopropylhydroxylamine in dimethylformamide is treated with sodiumhydride suspended in mineral oil, and the mixture is treated with8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineto give 8-nitro-1-[(diisopropylaminomethyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N¹-oxide.

Example 26: 8-Bromo-1-[(diethylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N¹ -oxide

In the manner given in Example 15,8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine is treated with a cold mixture ofN,N-diethylhydroxylamine and sodium hydride in dimethylformamide to give8-bromo-1-[(diethylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N¹ -oxide.

Example 27:8-Bromo-1-[(dimethylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N¹ -oxide

In the manner given in Example 16, a solution ofN,N-dimethylhydroxylamine in dimethylformamide is treated with sodiumhydride suspended in mineral oil, and the mixture is treated with8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-striazolo[4,3-a][1,4]benzodiazepine to give8-bromo-1[(dimethylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N¹ -oxide.

Example 28:8-Bromo-1-[(diethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N¹ -oxide

In the manner given in Example 15,8-bromo-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepineis treated with a cold mixture of N,N-diethylhydroxylamine and sodiumhydride in dimethylformamide to give 8-bromo-1-[(diethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N¹ -oxide.

Example 29: 8-Bromo-1-[(methylpropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N¹ -oxide

In the manner given in Example 16, a solution ofN-methyl-N-propylhydroxylamine in dimethylformamide is treated withsodium hydride suspended in mineral oil and the mixture is treated with8-chloro-1-(bromomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-bromo-1-[(methylpropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo [4,3-a][1,4]benzodiazepine.

Example 30: 8-Bromo-1-[(methylhydroxyamino)methyl]-6-(2-pyridyl)-4H-s-triazolo [4,3-a][1,4]benzodiazepine

In the manner given in Example 16, a solution of N-methylhydroxylaminein dimethylformamide is treated with sodium hydride suspended in mineraloil, and the mixture is treated with8-bromo-1-(chloromethy)-6-(2-pyridyl)-4H-s-triazolo4,3-a][1,4]benzodiazepine to give 8-bromo-1-[(methylhydroxyamino)methyl]-6-(2-pyridyl)-4H-s-triazolo [4,3-a][1,4]benzodiazepine.

Example 31: 8-Chloro-1-[(hydroxyamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 15,8-chloro-1-(chloromethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]-benzodiazepine is treated with a cold mixture of hydroxylamine andsodium hydride in dimethylformamide to give8-chloro-1-[(hydroxyamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 32:8-Bromo-1-[(ethylhydroxyamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

In the manner given in Example 16, a solution of N-ethylhydroxylamine indimethylformamide is treated with sodium hydride suspended in mineraloil, and the mixture is treated with8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give8-bromo-1-[(ethylhydroxyamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 33:8-Chloro-1-[(hydroxyamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 15,8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineis treated with a cold mixture of hydroxylamine and sodium hydride indimethylformamide to give8-chloro-1-[(hydroxyamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

In the manner given in the prior Examples 15 through 29, other1-[(dialkylamino methyl]-6-phenyl- or6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxides can besynthesized. Representative compounds, thus obtained, include:

8-bromo-6-(2,6-difluorophenyl)-1-[(dimethylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

8-chloro-6-(o-fluorophenyl)-1-[(methylethylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

8-chloro-6-(2,6-difluorophenyl)-1-[(dimethylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

6-(o-chlorophenyl)-1-[(dimethylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

6-(o-fluorophenyl)-1-[(methylisopropylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

8-nitro-6-phenyl-1-[(dimethylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

8-bromo-6-(o-chlorophenyl)-1-[(ethylpropylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

8-trifluoromethyl-6-phenyl-1-[(diethylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

8-fluoro-6-(o-chlorophenyl)-1-[(methylethylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

8-fluoro-6-(o-fluorophenyl)-1-[(dimethylamino)methyl]- 4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

7-chloro-6-(o-chlorophenyl)-1-[(dipropylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

9-bromo-6-phenyl-1-[(dipropylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

10-nitro-6-(o-fluorophenyl)-1-[(dimethylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

9-trifluoromethyl-6-(o-chlorophenyl)-1-[(diisopropylamino)-methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

8-chloro-6-(2-pyridyl)-1-[(methylpropylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

8-fluoro-6-(2-pyridyl)-1-[(methylisopropylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

8-nitro-6-(2-pyridyl)-1-[(dipropylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

8-trifluoromethyl-6-(2-pyridyl)-1-[(diisopropylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

7-nitro-6-(2-pyridyl)-1-[(dipropylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N¹ -oxide;

9-bromo-6-(2-pyridyl)-1[(diisopropylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N¹ -oxide;

10-chloro-6-(2-pyridyl)-1-[(diisopropylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide;

8-ethylthio-6-(2-pyridyl)-1-[(dimethylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

8-propylthio-6-(o-chlorophenyl)-1-[(diethylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

8-isopropylthio-6-(2,6-difluorophenyl)-1-[(methylethylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

8-methylthio-6-(2-pyridyl)-1-[(diethylamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide;

In the manner given in the prior Examples 30 through 33, other1-[(hydroxyamino)methyl]-6-phenyl- or 6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepines can be synthesized. Representativecompounds, thus obtained, include:

8-bromo-6-(2,6-difluorophenyl)-1-[(methylhydroxyamino)-methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(o-fluorophenyl)-1-[(methylhydroxyamino)-methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(2,6-difluorophenyl)-1-[(hydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

1-[(methylhydroxyamino)methyl]-4H-s-triazolo [4,3-a][1,4]benzodiazepine;

6-(o-fluorophenyl)-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-nitro-6-phenyl-1-[(propylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-bromo-6-(o-chlorophenyl)-1-[(isopropylhydroxyamino)-methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-trifluoromethyl-6-phenyl-1[(hydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(o-chlorophenyl)-1-[(methylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(o-fluorophenyl)-1-[(methylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(o-chlorophenyl)-1-[(ethylhydroxyamino)methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-bromo-6-phenyl-1-[(propylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

10nitro-6-(o-fluorophenyl)-1-[(methylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-trifluoromethyl-6-(o-chlorophenyl)-1-[(isopropylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

6-(2-pyridyl)-1-[(methylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-nitro-6-(2-pyridyl)-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-bromo-6 -(2-pyridyl)-1-[(isopropylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-trifluoromethyl-6-(2-pyridyl)-1-[(propylhydroxyamino)methyl]4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(2-pyridyl)-1-[(methylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(2-pyridyl)-1-[(ethylhydroxyamino)methy]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

7-chloro-6-(2-pyridyl)-1-[(isopropylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-bromo-6-(2-pyridyl)-1-[(hydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-methylthio-6-phenyl-1-[(methylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-ethylthio-6-(o-chlorophenyl)-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-propylthio-6-(2-pyridyl)-1-[(hydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

and the like.

Example 34: 8-Chloro-1-[[(diethylamino)oxy]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and8-chloro-1-[(ethylhydroxyamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine

A sample of 8-chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide hydrate (4.0 g.) was warmed in anoil bath under reduced pressure (23 mmHg). The temperature of the bathwas raised from 112° to 151° C. during 21 minutes and kept at 143°-151°C. for an additional 22 minutes. During this period the solid meltedwith bubbling. The amber melt was cooled and chromatographed on silicagel (200 g.) with 3% methanol-chloroform. The first compound eluted fromthe column was crystallized from ethyl acetate-Skellysolve B Hexanes togive 1.89 g., of8-chloro-1-[[(diethylamino)oxy]methyl]-6-phenyl-4H-s-triazolo-[4,3-a][1,4]benzodiazepineof melting pont 136-138.5° C. The analytical sample had melting point136°-139°.

Anal. calcd. for C₂₁ H₂₂ ClN₅ O: C, 63.71; H, 5.60; Cl, 8.95; N, 17.69.Found: C, 64.01; H, 5.91; Cl, 8.89; N, 17.62.

The second compound eluted from the column was crystallized from wetethyl acetate-Skellysolve B hexanes to give8-chloro-1-[(ethylhydroxyamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepinein three crops: 0.627 g. of melting point 154.5°-157° C.: 0.387 g. ofmelting point 152°-153.5° C. and 0.141 g. of melting point 150°-153.5°C. The analytical sample was crystallized once from wet ethylacetate-Skellysolve B hexanes and once from methanol-ethyl acetate andhad melting point 199°-200.5° C.

Anal. calcd. for C₁₉ H₁₈ ClN₅ O: C, 62.04; H, 4.93; Cl, 9.64; N, 19.04;Found: C, 61.95; H, 5.20; Cl, 9.51; N, 18.86.

Example 35:

8-Chloro-1-[[(diethylamino)oxy]methyl]-6(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine and8-chloro-1-[(ethylhydroxyamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 34,8-chloro-1-[(di-ethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepineN¹ -oxide is heated between 140°-155° C. to give8-chloro-1-[[(diethylamino)oxy]-methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepineand8-chloro-1-[(ethylhydroxyamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepinewhich are separated from each other by chromatography as in Example 34.

Example 36:

8-Fluoro-1-[[(ethylmethylamino)oxy]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepineand8-fluoro-1-[(methylhydroxyamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 34,8-fluoro-1-[(ethylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepineN¹ -oxide is heated between 140°-155° C. to give8-fluoro-1-[[(ethylmethylamino)oxy]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepineand8-fluoro-1-[(methylhydroxyamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepinewhich are separated from each other by chromatography as in Example 34.

Example 37:

8-Trifluoromethyl-1-[[(diethylamino)oxy]-methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepineand8-trifluoromethyl-1-[(ethylhydroxyamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine

In the manner given in Example 34,8-trifluoromethyl-1-[(diethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide is heated between 140°-155° C. to give8-trifluoromethyl-1-[[(diethylamino)oxy]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepineand8-trifluoromethyl-1-[(ethylhydroxyamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepinewhich are separated from each other by chromatography as in Example 34.

Example 38:

8-Nitro-1-[[(diethylamino)oxy]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineand8-nitro-1-[(ethylhydroxyamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 34,8-nitro-1-[(di-ethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepineN¹ -oxide is heated between 140°-155° C. to give8-nitro-1-[[(diethylamino)oxy]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineand8-nitro-1-[(ethylhydroxyamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepinewhich are separated from each other by chromatography as in Example 34.

Example 39:

8-Bromo-1-[[(ethylmethylamino)oxy]methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineand8-bromo-1-[(methylhydroxyamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

In the manner given in Example 34,8-bromo-1-[(ethylmethylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide is heated between 140°-155° C. to give8-bromo-1-[[(ethylmethylamino)oxy]methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine and 8-bromo-1-[(methylhydroxyamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine which are separated from each other bychromatography as in Example 34.

Example 40:

8-Chloro-1-[[(dipropylamino)oxy]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine and8-chloro-1-[(propylhydroxyamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 34,8-chloro-1-[(dipropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide is heated between 140°-155° C. to give8-chloro-1-[[(dipropylamino)oxy]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine and8-chloro-1-[(propylhydroxyamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4-benzodiazepine which are separated from each other bychromatography as in Example 34.

Example 41:

8-Chloro-1-[[(isopropylmethylamino)oxy]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and8-chloro-1-[(methylhydroxyamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 34,8-chloro-1-[(isopropylmethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine N¹ -oxide is heated between 140°-155° C. to give8-chloro-1-[[(isopropylmethylamino)oxy]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine and8-chloro-1-[(methylhydroxyamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine which are separated from each other bychromatography as in Example 34.

Example 42:

8-Bromo-1-[[(dipropylamino)oxy]methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine and8-bromo-1-[(propylhydroxyamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 34,8-bromo-1-[(dipropylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4, 3-a][1,4]benzodiazepine N¹ -oxide is heated between 140°-155° C. to give8-bromo-1-[[(dipropylamino)oxy]methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine and8-bromo-1-[(propylhydroxyamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine which are separated from each other bychromatography as in Example 34.

In the same manner given in Examples 34 to 42, other 6-phenyl- orrespectively6-(2-pyridyl)-1-[[(dialkylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepines (IIIB) can be prepared and isolated.Representative compounds thus obtained include:

8-bromo-6-phenyl-1-[[(diethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(o-fluorophenyl)-1-[[(ethylmethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(2,6-difluorophenyl)-1-[[(diethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

6(o-chlorophenyl)-1-[[(diethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

6-(o-fluorophenyl)-1-[[(ethylmethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-nitro-6-phenyl-1-[[(diethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-bromo-6-(o-chlorophenyl)-1-[(ethylmethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-trifluoromethyl-6-phenyl-1-[[(diethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(o-chlorophenyl)-1-[(ethylpropylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(o-fluorophenyl)-1-[[(ethylisopropylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

7-chloro-6-(o-chlorophenyl)-1-[[(diethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-bromo-6-phenyl-1-[[(diethylamino)oxy]methyl]-4H-s-triazolo[4,3a-][1,4]benzodiazepine;

10-nitro-6-(o-fluorophenyl)-1-[[diethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-trifluoromethyl-6-(o-chlorophenyl)-1-[[(diethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(2-pyridyl)-1-[[(diethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(2-pyridyl)-1-[[(ethylmethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-nitro-6-(2-pyridyl)-1-[[diethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-trifluoromethyl-6-(2-pyridyl)-1-[[(diethylamino)oxy]methyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

7-nitro-6-(2-pyridyl)-1-[[(ethylmethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-bromo-6-(2-pyridyl)-1-[[(diethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

10-chloro-6-(2-pyridyl)-1-[[(diethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-bromo-6-phenyl-1-[[(dipropylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(o-fluorophenyl)-1-[[(ethylpropylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(2,6-difluorophenyl)-1-[[(methylpropylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

6-(o-chlorophenyl)-1-[[(dipropylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-nitro-6-phenyl-1-[[(methylpropylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(o-chlorophenyl)-1-[(ethylpropylamino)oxy]methyl]4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(o-fluorophenyl)-1-[(methylpropylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

7-chloro-6-(o-chlorophenyl)-1-[[(dipropylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

10-nitro-6-(o-fluorophenyl)-1-[[(dipropylamino)oxy]-methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-trifluoromethyl-6-(o-chlorophenyl)-1-[[(dipropylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(2-pyridyl)-1-[[(dipropylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(2-pyridyl)-1-[[(methylpropylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

7-nitro-6-(2-pyridyl)-1-[[(ethylpropylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-bromo-6-(2-pyridyl)-1-[[(dipropylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-methylthio-6-phenyl-1-[[(diethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-methylthio-6-(2-pyridyl)-1-[[(ethylmethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-ethylthio-6-(o-chlorophenyl)-1-[[(diethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-propylthio-6-phenyl-1-[[(methylpropylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

1-[[(diethylamino)oxy]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-methylthio-6-(2-pyridyl)-1-[[(diethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;and the like.

Also in the same manner given in Examples 32 to 40, other 6-phenyl- orrespectively6-(2-pyridyl)-1-[(alkylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepines(V) can be prepared. Representative compounds thus obtained include:

8-bromo-6-phenyl-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(o-fluorophenyl)-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(2,6-difluorophenyl)-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

6-(o-chlorophenyl)-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

6-(o-fluorophenyl)-1-[(methylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-nitro-6-phenyl-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-bromo-6-(o-chlorophenyl)-1-[(methylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-trifluoromethyl-6-phenyl-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(o-chlorophenyl)-1-[(methylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(o-fluorophenyl)-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

7-chloro-6-(o-chlorophenyl)-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-bromo-6-phenyl-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

10-nitro-6-(o-fluorophenyl)-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-trifluoromethyl-6-(o-chlorophenyl)-1-[(methylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(2-pyridyl)-1-[(methylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(2-pyridyl)-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-nitro-6-(2-pyridyl)-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-trifluoromethyl-6-(2-pyridyl)-1-[(methylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

7-nitro-6-(2-pyridyl)-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-bromo-6-(2-pyridyl)-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

10-chloro-6-(2-pyridyl)-1-[(methylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8bromo-6-phenyl-1-[(propylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(o-fluorophenyl)-1-[(propylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(2,6-difluorophenyl)-1-[(propylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

6-(o-fluorophenyl)-1-(propylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-nitro-6-phenyl-1-[(propylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-bromo-6-(o-chlorophenyl)-1-[(propylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-trifluoromethyl-6-phenyl-1-[(propylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(o-chlorophenyl)-1-[(isopropylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(o-fluorophenyl)-1-[(isopropylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

7-chloro-6-(o-chlorophenyl)-1-[(isopropylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-trifluoromethyl-6-(o-chlorophenyl)-1-[(isopropylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(2-pyridyl)-1-[(isopropylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-methylthio-6-phenyl-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-ethylthio-6-(o-chlorophenyl)-1-[(methylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-propylthio-6-(2-pyridyl)-1-[(propylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-isopropylthio-6-(o-fluorophenyl)-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-methylthio-6-(o-chlorophenyl)-1-[(methylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

1-[(ethylhydroxyamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-methylthio-6-(2-pyridyl)-1-[(ethylhydroxyamino)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

and the like.

Example 43:

8-Chloro-1-[[(dimethylamino)oxy]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine

A sample of8-chloro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide hydrate (0.4 g.) was warmed under reduced pressure (34 mm) at151°-161° C. for 8 minutes. During this time the solid melted withbubbling. The cooled melt was chromatographed on silica gel (50 g.) with3% methanol-97% chloroform. The product thus obtained was crystallizedfrom ethyl acetate-Skellysolve B (hexanes) to give8-chloro-1-[[(dimethylamino)oxy]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepinein two crops: 0.236 g. of melting point 175.5°-176.5° C. and 0.030 g. ofmelting point 174° C. The analytical sample had a melting point 175° C.

Anal. calcd. for C₁₉ H₁₈ ClN₅ O: C, 62.04; H, 4.93; Cl, 9.64; N, 19.04.Found: C, 62.20; H, 5.06; Cl, 9.55; H, 19.17.

Example 44:

8-Chloro-1-[[(dimethylamino)oxy]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 43,8-chloro-1-[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide was heated to 160° C. to give8-chloro-1-[[(dimethylamino)oxy]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 45:8-Fluoro-1-[[(dimethylamino)oxy]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 43,8-fluoro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide was heated to 160° C. to give8-fluoro-1-[[(dimethylamino)oxy]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 46:

8-Trifluoromethyl-1-[[(dimethylamino)oxy]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 43,8-trifluoromethyl-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide was heated to 160° C. to give8-trifluoromethyl-1-[[(dimethylamino)oxy]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 47:8-Nitro-1-[[(dimethylamino)oxy]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 43,8-nitro-1-[[(dimethylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide was heated to 160° C. to give8-nitro-1-[[(dimethylamino)oxy]methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

Example 48:8-Bromo-1-[[(dimethylamino)oxy]methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine

In the manner given in Example 43,8-bromo-1-[(dimethylamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepineN¹ -oxide was heated to 160° C. to give8-bromo-1-[[(dimethylamino)oxy]methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.

In the same manner given in Examples 43 to 48, combined with Example 15,other 6-phenyl- or respectively6-(2-pyridyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepines(IIIB) can be prepared. Representative compounds thus obtained include:

8-methylthio-6-phenyl-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-ethylthio-6-(o-chlorophenyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-propylthio-6-(2-pyridyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-isopropylthio-6-(o-fluorophenyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-methylthio-6-(2-pyridyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-bromo-6-phenyl-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(o-fluorophenyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(2,6-difluorophenyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-trifluoromethyl-6-(o-chlorophenyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

6-(o-fluorophenyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-nitro-6-phenyl-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-bromo-6-(o-chlorophenyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-trifluoromethyl-6-phenyl-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(o-chlorophenyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(o-fluorophenyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

7-chloro-o-(o-chlorophenyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-bromo-6-phenyl-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

10-nitro-6-(o-fluorophenyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-trifluoromethyl-6-(o-chlorophenyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-chloro-6-(2-pyridyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-fluoro-6-(2-pyridyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-nitro-6-(2-pyridyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

8-trifluoromethyl-6-(2-pyridyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

7-nitro-6-(2-pyridyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

9-bromo-6-(2-pyridyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

10-chloro-6-(2-pyridyl)-1-[[(dimethylamino)oxy]methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine;

and the like.

Example 49:0-[(8-Chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime

A stirred mixture of8-chloro-1-[(aminooxy)methyl]6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine(3.40 g., 0.01 mole), acetic acid (0.6 g., 0.01 mole), 37% aqueousformaldehyde (5 ml.) and absolute ethanol (30 ml.) was kept at ambienttemperature for 1 hour, and concentrated in vacuo. The residue was mixedwith water, neutralized with sodium bicarbonate and extracted withchloroform. The extract was washed with brine, dried over anhydroussodium sulfate and concentrated. The residue was crystallized from ethylacetate to give the0-[(8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehyde oxime of melting point 208.5°-210° C.

Anal. calcd. for C₁₈ H₁₄ ClN₅ O: C, 61.46; H, 4.01; Cl, 10.08; N, 19.91.Found: C, 61.56; H, 4.04; Cl, 9.98; N, 19.97.

Example 50:

0-[(8-Chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime

A stirred mixture of8-chloro-1-[(aminooxy)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine(3.40 g., 0.01 mole), acetic acid (0.6 g., 0.01 mole), acetone (3 ml.)and absolute ethanol (30 ml.) was refluxed under nitrogen for 1 hour andconcentrated in vacuo. The residue was mixed with water, neutralizedwith sodium bicarbonate and extracted with chloroform. The extract waswashed with brine, dried over anhydrous sodium sulfate and concentrated.The residue was crystallized from ethyl acetate-Skellysolve B hexanes togiveO-[(8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime of melting point 168.5°-170° C.

Anal. calcd. for C₂₀ H₁₈ ClN₅ O: C, 63.24; H, 4.78; Cl, 9.33; N, 18.44.Found: C, 62.74; H, 4.81; Cl, 9.44; N, 18.51.

Example 51:

0-[(8-Chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime

In the manner given in Example 49,8-chloro-1-[(aminooxy)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,acetic acid, formaline, and ethanol are reacted to give0-[(8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)-methyl]formaldehydeoxime.

Example 52:0-[(8-Chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime

In the manner given in Example 50,8-chloro-1-[(aminooxy)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,acetic acid, acetone and ethanol are reacted to give0-[(8-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime.

Example 53:0-[(8-Fluoro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]propionaldehydeoxime

In the manner given in Example 49, 8-fluoro-1-[(aminooxy)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine,acetic acid, propionaldehyde, (instead of the formaldehyde of Example49) and ethanol are reacted to give0-[(8-fluoro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]propionaldehydeoxime.

Example 54:0-[(8-Nitro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]methylethyl ketone oxime

In the manner given in Example 50,8-nitro-1-[(aminooxy)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine,acetic acid, methyl ethyl ketone (instead of the acetone of Example 50)and ethanol are reacted to give O-[(8-nitro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a] [1,4]benzodiazepin-1-yl]methyl ethyl ketone oxime.

Example 55: O-[(8-Trifluoromethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4[benzodiazepin-1-yl)methyl]formaldehydeoxime

In the manner given in Example 49, 8-trifluoromethyl-1-[(aminooxy)methyl]- 6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, acetic acid, formaline and ethanol are reacted togive O-[ (8-trifluoromethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl] formaldehyde oxime.

Example 56: O-[(8-Bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehyde oxime

In the manner given in Example 49, 8-bromo-1-[ (aminooxy)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, acetic acid,formaline and ethanol are reacted to give O-[(8-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehyde oxime.

Example 57; O-[ (8-Bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl] acetone oxime

In the manner given in Example 50, 8-bromo-1-[(aminooxy)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, acetic acid, acetone and ethanol are reacted togive O-[(8-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime.

Example 58: O-[(8-Bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]methyl ethyl ketone oxime

In the manner given in Example 50, 8-bromo-1-[(aminooxy)methyl[-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine,acetic acid, methyl ethyl ketone and ethanol are reacted to give O-[(-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1yl)methyl]methyl ethyl ketoneoxime.

In the manner given in the preceding Examples 47 to 58, other Schiffsbases of compounds of formula IIIA can be made. Representativecompounds, thus obtained, include:

O-[(8-bromo-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime;

O-[ (8-chloro-6-(o-fluorophenyl)4H-s-triazolo[4,3-a][(1,4]benzodiazepin-1-yl)methyl]formaldehyde oxime;

O-[(8-chloro-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime;

O-[(6-)o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime;

O-[ 6-o-fluoropheny)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehyde oxime;

O-[(8-nitro-6-phenyl-4H-s-triazolo[4,3-a][1,4];benzodiazepin-1yl)methyl]formaldehyde oxime;

O-[(8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepin-1-yl)methyl]formaldehyde oxime;

O-[(8-trifluoromethyl-6-phenyl-4H-s-triazolo[4,3a][1,4]-benzodiazepin-1yl)methyl]formaldehyde oxime;

O-[(8-fluoro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepin-1-yl)methyl]formaldehyde oxime;

O-[(8-fluoro-6-(o-fluorophenyl)-4H-s-triazolo[4,3a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime;

O-[(7-chloro-6-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1yl)methyl]formaldehydeoxime;

O-[(9-bromo-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime;

O-[(10-nitro-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime;

O-[(9-trifluoromethyl-6-(o-chlorophenyl)-4H-s-triazolo-[4,3a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime;

O[(8-chloro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime;

O-[(8-fluoro-6-(2-pyridyl)-4H-s-triazolo[4,3a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime;

O-[(8-nitro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime;

O-[-(8-trifluoromethyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime;

O-[(7-nitro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime;

O-[(9-bromo-6-(2-pyridyl)-4-H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime;

O-[(10-chloro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime;

O-[(8-bromo-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

O-[(8-chloro-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

O-[(8-chloro-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

O-[(6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1yl)methyl]acetoneoxime;

0-[(6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

0-[(8-nitro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

0-[(8-bromo-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

0-[ (8-trifluoromethyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetone oxime;

0-[(8-fluoro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

0-[(8-fluoro-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4)-benzodiazepin-1-yl)methyl]acetoneoxime;

0-[(7-chloro-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

0[(9-bromo-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

0[(10-nitro-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

0-[(9-trifluoromethyl-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl(methyl]acetoneoxime;

0-[-chloro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

0-[(8-fluoro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

0-[-(8-nitro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

0-[(8-trifluoromethyl-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

0-[(7-nitro-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine-1-yl)methyl]acetoneoxime;

O-[(9-bromo-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

O-[(10-chloro-6-(2pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

O-[(8-methylthio-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

O-[(8-ethylthio-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4benzodiazepin-1-yl)methyl]formaldehyde oxime;

O-[(8-propylthio-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneoxime;

O-[(8-isopropylthio-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]acetoneomixe;

O-[(6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepin-1-yl)methyl]formaldehydeoxime; and the like.

Example 59:8-Chloro-1-[[(methylamino)oxy]methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine

A stirred solution of8-chloro-1-[(aminooxy)methyl]6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine(0.02 mole) in dry dimethylformamide (50 ml.) is cooled in an ice bathunder nitrogen and treated successively with a 57% mineral oilsuspension of sodium hydride (0.84 g,. 0.02 mole) and methyliodide (0.02mole). The mixture is allowed to come slowly to ambient temperature andstand for 18 hours. It is then concentrated in vacuo. The residue ischromatographed on silica gel with methanol to give8-chloro-1-[[(methylamino)oxy]methyl]6-phenyl-4H-s-triazolo]4,3-a][1,4]benzodiazepine.

Using the procedure of Example 59 but substituting other1-[(aminooxy)methyl]- 6-phenyl- or6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepines for8-chloro-1-[(aminooxy)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepineand other alkyl halides for methyl iodide other1-[[(monoalkylamino)oxy]methyl]-6-phenyl- or6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepines of formula IIIcan be prepared.

The pharmacologically acceptable acid addition salts of compounds offormulae III, IV, V, VA, and VI can be prepared and isolated byconventional processes, such as reacting a compound of said formula witha selected pharmacologically acceptable acid. Such acids includehydrochloric, hydrobromic, phosphoric, sulfuric, acetic, tartaric,lactic, citric, malic, maleic, methanesulfonic, benzenesulfonic,cyclohexanesulfamic acids, toluensulfonic, and the like. The reaction isconveniently performed in an organic solvent, e.g. ether, dioxane, ortetrahydrofuran, ethanol, methanol, or ethyl acetate; the salts can berecovered by crystallization, precipitation or evaporation of thesolvent. These salts are useful in the same manner as the free base.

I claim:
 1. A compound of the formula VA: ##STR12## wherein R_(o) ishydrogen or alkyl of 1 to 3 carbon atoms, inclusive; wherein R₁ ishydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl, or alkylthio inwhich the alkyl moiety is of 1 to 3 carbon atoms, inclusive; and whereinR₂ is phenyl, o-chlorophenyl, o-fluorophenyl, 2,6-difluorophenyl or2-pyridyl, or the pharmacologically acceptable acid addition saltsthereof.
 2. A compound according to claim 1 of the formula VB: ##STR13##wherein R₁ is hydrogen, fluoro, chloro, bromo, nitro, trifluoromethyl,or alkylthio in which the alkyl moiety is of 1-3 carbon atoms,inclusive; wherein R₂ is phenyl, o-chlorophenyl, o-fluorophenyl,2,6-difluorophenyl, or 2-pyridyl; and wherein R₄ is methyl or ethyl, orthe pharmaceutically acceptable acid addition salts thereof.
 3. Thecompound of claim 2, wherein R₁ is bromo, R₂ is 2-pyridyl, R₄ is ethyl,and the compound is therefore8-bromo-1-[(ethylhydroxyamino)methyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.4. A compound according to claim 2 of the formula VC: ##STR14## whereinR'₁ is hydrogen, fluoro, chloro, or trifluoromethyl; wherein R₃ ishydrogen, chloro, or fluoro; and wherein R₄ is methyl or ethyl, and thepharmaceutically acceptable acid addition salts thereof.
 5. The compoundaccording to claim 4, wherein R'₁ is chloro, R₃ is hydrogen and R₄ isethyl, and the compound is therefore8-chloro-1-[(ethylhydroxyamino)methyl]6-phenyl-4-H-s-triazolo[4,3-a][1,4]benzodiazepine.6. The compound according to claim 4, wherein R'₁ and R₃ are chloro, R₄is ethyl, and the compound is therefore8-chloro-1-[(ethylhydroxyamino)methyl]-6-(o-chlorophyl)4H-s-triazolo[4,3-a][1,4]benzodiazepine.
 7. The compound according toclaim 4, wherein R'₁ is fluoro, R₃ is hydrogen, R₄ is ethyl, and thecompound is therefore8-fluoro-1-[(ethylhydroxyamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.8. The compound according to claim 4, wherein R'₁ is chloro, R₃ ishydrogen, R₄ is methyl, and the compound is therefore8-chloro-1-[(methylhydroxyamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.